Career Summary

Biography

Prof. Marjorie Walker currently holds the position of Professor of Anatomical Pathology in the School of Medicine and Public Health at the University of Newcastle. Prior to her appointment at Newcastle, Professor Walker held concurrent appointments as Reader and Honorary Consultant with the Histopathology Centre for Pathology at Imperial College London and Imperial College Healthcare NHS Trust Cellular Pathology Department, St Mary’s Hospital. She also served as Assistant Admissions Tutor at Imperial College. Her diagnostic specialty areas are GI pathology, Uropathology and Dermatopathology. Professor Walker has also previously held the position of Honorary Associate Professor in the Faculty of Medicine, University of Sydney, Australia (2008-11).

Research ExpertiseMy expertise as a histopathologist is in interpretation of clinical or molecular events in tissue sections, correlating both routine pathology and immunocytochemistry to demonstrate particular cells or their function or secretion with clinical patient data. I principally work in gastrointestinal and urological pathology, particularly prostate cancer. In the last 10 years I have developed expertise in upper gastrointestinal pathology and my current research is focused on finding biomarkers and pathways in functional bowel diseases, named functional as there is no discernible organic pathology.Over the next 5 years I plan to complete the investigation of functional bowel disorders and other gastrointestinal disorders to unravel the pathology which occurs in these diseases, and hope to elucidate the cause of these distressing conditions with the aim of devising effective agents for treatment. I am also working on coeliac disease and plan to continue defining parameters for diagnosis of coeliac disease in conjuction with the International Coeliac Definitions Group.

Teaching ExpertiseMy teaching experience extends across Undergraduate, Masters and Postgraduate levels. I have taught histopathology to undergraduate and graduate entry students at Imperial College in years 1 - 5, from basic principles to systems pathology. I contribute to course design, exam development and marking - as a senior examiner in pathology at Imperial College I have responsibility for setting and marking all years of undergraduates, and attend group marking sessions and examinations meetings. As Divisional Head of Teaching for Investigative Science (1999-2003), in the curriculum review at that time, I ensured that pathology was introduced as a standalone course, comprising lectures, tutorials and clinicopathological conferences to ensure that students see the integration of clinicians and the different pathology disciplines. I have lectured on principles of pathology to wide ranging groups, for example, perioperative surgical practitioners and ophthalmology FY2s. I also give invited lectures at National and International meetings.

Administrative ExpertiseI have extensive administrative experience, having served on numerous committees and held the position of Assistant Admissions tutor at Imperial College. In this role, I was the sole clinician on the team and my duties included:

• Interviewer training

• Participation in Graduate Entry Open Days to promote the course at Imperial College.

I am also the UK representative for the European Society of Pathology Gastrointestinal Working Group (2005 – Present), which decides on topics of interest for short courses, symposia and slide seminars at the now yearly European Congress of Pathology. I have organised all types of sessions, which involves inviting histopathologists from Europe to participate. I undertake review of papers for Gut, American Journal of Gastroenterology, Alimentary Pharmacology and Therapeutics, Histopathology, Clinical Gastroenterology and Hepatology, Journal of Clinical Pathology, European Journal of Gastroenterology and Hepatology, Clin Chem Acta, European Journal of Surgical Oncology and the British Journal of Medical and Surgical Urology. I also review grants for CRUK and NHMRC (Australia) and am an Editorial Board member of Alimentary Pharmacology and Therapeutics.

• Chile/ Leeds UK - I am an expert advisor to the Content study – This is funded by the EU, a study on iron deficiency and infection in the gastrointestinal tract in children in Brazil, Chile and London (Professor Jean Crabtree, Leeds, UK, Dr Paul Harris, Santiago, Chile).

• Member, International Coeliac Definitions Group – an international group of physicians with a prime interest in coeliac disease, defining management and diagnosis of coeliac disease.

Irritable bowel syndrome (IBS) is a functional disorder defined by symptoms in the absence of overt pathology. Colonic spirochetosis (CS), defined by histologic observation of spirochetal strains of Brachyspira in colonic biopsies, is uncommon and considered of doubtful significance. We aimed to determine the prevalence of CS in the general population, identify subtle colon pathologies, and evaluate a link with symptoms of IBS. Colonoscopy was performed in 745 subjects (aged 19-70 years, mean age 51 years, 43% male) with biopsies (ileum and 4 colonic sites) from a random population sample, Stockholm, Sweden, who completed a validated questionnaire of gastrointestinal symptoms; IBS was identified by Rome III criteria. CS was identified by histology and immunohistochemistry. In a general population, 17 individuals (2.28%; 95% confidence interval, 1.2%-3.5%) were diagnosed as having CS by histology; 6 (35%) had IBS. CS was always present in the sigmoid colon, but only 14 rectal biopsies. Eosinophils were increased in colon biopsies in CS cases versus controls, in the transverse (P =.02), sigmoid colon (P =.001), and rectum (P =.0005) with subepithelial eosinophil clusters (P =.053). Lymphoid follicles (at any site) were present in 13 CS (P =.0003). There was a 3-fold increased risk of IBS in CS (odds ratio, 3.59; 95% confidence interval, 1.27-10.11; P =.015). Polyps and diverticular disease were similar in CS cases and controls. The prevalence of CS in a general population is 2% and associated with nonconstipating IBS. Colonic eosinophilia with lymphoid follicles may signify the presence of CS.

Infiltration of the tumor microenvironment by nerve fibers is an understudied aspect of breast carcinogenesis. In this study, the presence of nerve fibers was investigated in a co... [more]

Infiltration of the tumor microenvironment by nerve fibers is an understudied aspect of breast carcinogenesis. In this study, the presence of nerve fibers was investigated in a cohort of 369 primary breast cancers (ductal carcinomas in situ, invasive ductal and lobular carcinomas) by immunohistochemistry for the neuronal marker PGP9.5. Isolated nerve fibers (axons) were detected in 28% of invasive ductal carcinomas as compared to only 12% of invasive lobular carcinomas and 8% of ductal carcinomas in situ (p=0.0003). In invasive breast cancers, the presence of nerve fibers was observed in 15% of lymph node negative tumors and 28% of lymph node positive tumors (p=0.0031), indicating a relationship with the metastatic potential. In addition, there was an association between the presence of nerve fibers and the expression of nerve growth factor (NGF) in cancer cells (p=0.0001). Invitro, breast cancer cells were able to induce neurite outgrowth in PC12 cells, and this neurotrophic activity was partially inhibited by anti-NGF blocking antibodies. In conclusion, infiltration by nerve fibers is a feature of the tumor microenvironment that is associated with aggressiveness and involves NGF production by cancer cells. The potential participation of nerve fibers in breast cancer progression needs to be further considered.

Functional gastrointestinal disorders (FGIDs) are common and distressing. They are so named because a defined pathophysiology in terms of structural or biochemical pathways is lac... [more]

Functional gastrointestinal disorders (FGIDs) are common and distressing. They are so named because a defined pathophysiology in terms of structural or biochemical pathways is lacking. Traditionally FGIDs have been conceptualized as brainÂ¿gut disorders, with subgroups of patients demonstrating visceral hypersensitivity and motility abnormalities as well as psychological distress. However, it is becoming apparent that there are certain structural or biochemical gut alterations among subsets with the common FGIDs, most notably functional dyspepsia (FD) and irritable bowel syndrome (IBS). For example, a sodium channel mutation has been identified in IBS that may account for 2Â¿% of cases, and subtle intestinal inflammation has been observed in both IBS and FD. Other research has implicated early life events and stress, autoimmune disorders and atopy and infections, the gut microbiome and disordered mucosal immune activation in patients with IBS or FD. Understanding the origin of symptoms in FGIDs will allow therapy to be targeted at the pathophysiological changes, not at merely alleviating symptoms, and holds hope for eventual cure in some cases. For example, there are promising developments in manipulating the microbiome through diet, prebiotics and antibiotics in IBS, and testing and treating patients for Helicobacter pylori infection remains a mainstay of therapy in patients with dyspepsia and this infection. Locally acting drugs such as linaclotide have been an advance in treating the symptoms of constipation-predominant IBS, but do not alter the natural history of the disease. A role for a holistic approach to patients with FGIDs is warranted, as brain-to-gut and gut-to-brain pathways appear to be activated.

Nerve infiltration is essential to prostate cancer progression, but the mechanism by which nerves are attracted to prostate tumors remains unknown. We report that the precursor of... [more]

Nerve infiltration is essential to prostate cancer progression, but the mechanism by which nerves are attracted to prostate tumors remains unknown. We report that the precursor of nerve growth factor (proNGF) is overexpressed in prostate cancer and involved in the ability of prostate cancer cells to induce axonogenesis. A series of 120 prostate cancer and benign prostate hyperplasia (BPH) samples were analyzed by IHC for proNGF. ProNGF was mainly localized in the cytoplasm of epithelial cells, with marked expression in cancer compared with BPH. Importantly, the proNGF level positively correlated with the Gleason score (n = 104, tB = 0.51). A higher level of proNGF was observed in tumors with a Gleason score of =8 compared with a Gleason score of 7 and 6 (P < 0.001). In vitro, proNGF was detected in LNCaP, DU145, and PC-3 prostate cancer cells and BPH-1 cells but not in RWPE-1 immortalized nontumorigenic prostate epithelial cells or primary normal prostate epithelial cells. Co-culture of PC12 neuronal-like cells or 50B11 neurons with PC-3 cells resulted in neurite outgrowth in neuronal cells that was inhibited by blocking antibodies against proNGF, indicating that prostate cancer cells can induce axonogenesis via secretion of proNGF. These data reveal that ProNGF is a biomarker associated with high-risk prostate cancers and a potential driver of infiltration by nerves.

A multidisciplinary panel of 18 physicians and 3 nonphysicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.

Background: Eosinophilic esophagitis (EoE) is an inflammatory disorder of the esophagus defined by eosinophil infiltration and tissue remodeling with resulting symptoms of esophag... [more]

Background: Eosinophilic esophagitis (EoE) is an inflammatory disorder of the esophagus defined by eosinophil infiltration and tissue remodeling with resulting symptoms of esophageal dysfunction. TNF-related apoptosis-inducing ligand (TRAIL) promotes inflammation through upregulation of the E3 ubiquitin-ligase midline-1 (MID1), which binds to and deactivates the catalytic subunit of protein phosphatase 2Ac, resulting in increased nuclear factor Â¿B activation. Objective: We sought to elucidate the role of TRAIL in EoE. Methods: We used Aspergillus fumigatus to induce EoE in TRAIL-sufficient (wild-type) and TRAIL-deficient (TRAIL-/-) mice and targeted MID1 in the esophagus with small interfering RNA. We also treated mice with recombinant thymic stromal lymphopoietin (TSLP) and TRAIL. Results: TRAIL deficiency and MID1 silencing with small interfering RNA reduced esophageal eosinophil and mast cell numbers and protected against esophageal circumference enlargement, muscularis externa thickening, and collagen deposition. MID1 expression and nuclear factor Â¿B activation were reduced in TRAIL-/- mice, whereas protein phosphatase 2Ac levels were increased compared with those seen in wild-type control mice. This was associated with reduced expression of CCL24, CCL11, CCL20, IL-5, IL-13, IL-25, TGFB, and TSLP. Treatment with TSLP reconstituted hallmark features of EoE in TRAIL-/- mice and recombinant TRAIL induced esophageal TSLP expression invivo in the absence of allergen. Post hoc analysis of gene array data demonstrated significant upregulation of TRAIL and MID1 in a cohort of children withEoE compared with that seen in controls. Conclusion: TRAIL regulates MID1 and TSLP, inflammation, fibrosis, smooth muscle hypertrophy, and expression ofinflammatory effector chemokines and cytokines inexperimental EoE.